What if any role remains for niacin after AIM HIGH?
The AIM HIGH Study provides no evidence for benefit from niacin in the very patients in whom this drug is most commonly used. However, the differences in administration of LDL-lowering therapies in the two treatment groups represents a serious design flaw. Furthermore, the study was underpowered and stopped at a point where the lower limit of the 95% confidence interval could not rule out a modest benefit. The decision to stop the trial prematurely for futility was unwise and deprived the medical community of a more robust assessment of the benefits and risks of niacin treatment. Despite these flaws, it seems unlikely that niacin represents an overall benefit to patients and its routine usage should be discouraged.
Quite frankly, AIM-HIGH doesn’t change much for me, but rather underscores the continued necessary focus on LDL reduction with statins to improve CV outcomes. I will likely continue to use niacin (a) in combination with statins in very high risk individuals with far higher LDL levels than seen in AIM-HIGH and (b) alone in statin-intolerant patients or individuals with extremely elevated Lp(a). None of these groups were included in this study.
Niacin will still be useful as (a) a second-line therapy in patients whose LDL-C or non-HDL cholesterol is not at goal despite maximally tolerated statin therapy or (b) as a first-line agent in patients who cannot tolerate a statin. Niacin did not show benefit as an add-on therapy in AIM-HIGH when the baseline LDL-C was 70. It may be beneficial when the baseline LDL-C on maximally tolerated statin is 100.
I think that this study also tells us that there is little future role for serial carotid IMT testing to determine the best cholesterol lowering therapy. The ARBITER 6 – HALTS investigators were thrilled with a 0.014 mm improvement in carotid IMT vs. no change with ezetimibe. The AIM-HIGH clinical trial showed that this was associated with no benefit over a three year period, unfortunately. The insightful editorial that Erin Michos and I wrote about ARBITER 6 in the NEJM seems to have been right on the mark. I wonder if we will ever get an apologies from the few niacin zealots who were so critical of what we wrote. Vindication is a nice feeling, but I wish that the clinical trial results had been positive so that we could help our patients more.
William Boden, MD (PI of AIM HIGH)
An important therapeutic role clearly remains for niacin. What does AIM HIGH tell us then? If you are a patient with stable, non-acute cardiovascular disease who meets an indication for statin therapy AND who is able to achieve and maintain a very low level of on-treatment LDL-C as we attained in AIM-HIGH (in the low 60 mg/dL range), then there is no clinical benefit for HDL-C raising therapy with niacin to further reduce clinical events over and above what is achieved by statin therapy alone.
But how many patients fall into the above category? Data from 3 large data sets/registries (GE Healthcare, United Healthcare, NHANES) indicate that only 13% to 19% of high-risk CHD patients actually can achieve/maintain the very low levels of LDL-C we accomplished in our study. One can only apply the results of RCTs to the population that we actually enrolled in the trial and should not extrapolate the study findings to subgroups of patients who were not enrolled or those who, by trial design, were excluded (e.g., AMI or ACS patients).
AIM-HIGH also enrolled only a small percentage of women (15%) and an even smaller percentage of ethnic minorities (8%)—important subsets for whom these results may not apply.
Lastly, AIM-HIGH was plagued by an intensity and duration of prior statin therapy that may have made it difficult to discern an incremental clinical treatment effect, especially given the very low mean starting LDL-C in the 94% of trial patients who had been on a statin for at least 1 year (76%). Indeed, many of these patients had been on statin therapy for much longer (40% for 5 or more years). Such long-term therapy, superimposed on a background of optimal medical therapy and secondary prevention (e.g., ASA and antiplatelet drugs, beta-blockers, ACE inhibitors and ARBs), may have, in the aggregate, converted vulnerable coronary plaques destined to rupture (as the putative inciting event/trigger to clinical events) into stable, quiescent plaques where the the soluble constituents of the necrotic core was “delipidated.” This is yet another reason we should be cautious in how we apply the results of AIM-HIGH to the broader population of patients that we did not enroll. Niacin still has a therapeutic role to favorably alter the lipid profile in high-risk patients and we need to reserve judgment on the long-term usage of this agent, pending the results of the ongoing HPS-2 THRIVE Trial.